Project Summary The long-term goal of these studies is to understand how altered cerebral hemodynamics and oxygen metabolism contribute to neurological disease, and identify their role in the pathophysiology of migraine. Our overall hypothesis is that cerebral blood flow (CBF) and oxygen metabolism (CMRO2) are abnormal in migraine, and this affects local cerebral tissue oxygenation (PtO2). Further, that the CBF / CMRO2 coupling in response to a visual stimulus is also abnormal in migraine. During recent studies we observed hypoperfusion and hypometabolism during migraine without aura, but a greater decline in metabolism resulted in a small increase in local tissue oxygenation during the headache phase. Following sumatriptan both CBF and CMRO2 were normalized. Following a visual stimulus, we observed an increased CBF response, and increased CBF/CMRO2 coupling response, possibly related to neuronal hyperexcitability. Neither of these stimulus-induced changes responded to sumatriptan. Our first specific aim is to characterize the changes in steady-state CBF and CMRO2 during baseline, prodrome symptoms, headache symptoms and in response to sumatriptan, and determine how this affects tissue oxygenation at different phases of migraine. Our second aim is to characterize the CBF/CMRO2 coupling in response to a high contrast vs. a low contrast visual stimulus, again at different phases of migraine. A third aim is to address changes in resting state BOLD synchrony during migraine, as an indication of increased cortical synchrony during migraine. Also to examine a phenomenon of non-aura spreading waves of BOLD signal attenuation, from resting state fMRI data. These studies will be conducted in 10 women with menstrual migraine, and 10 controls. These studies present a new approach to address basic mechanistic questions in migraine pathophysiology. The endpoint of this exploratory work is the characterization of CBF and CMRO2 coupling and its impacts on cerebral tissue oxygenation, as well as the role of BOLD synchrony, during the evolution / treatment of symptoms in menstrual migraine. This will establish the basis for applying these novel MRI tools to evaluate the natural history or response to therapy more widely in migraine disorders.